Angiotensin II receptor antagonist for the prevention or treatment of systemic diseases in cats

ABSTRACT

The present invention relates to a method of prophylaxis or treatment of systemic diseases in cats, wherein the method comprising administration of a therapeutically effective amount of angiotensin II receptor 1 (AT-1) antagonist (sartan) to a cat in need of such a treatment.

RELATED APPLICATIONS

This application claims priority to European Application No. EP06121905.1, filed Oct. 6, 2006, the teachings and content of which arehereby incorporated by reference herein.

FIELD OF INVENTION

The present invention relates to the field of veterinary medicine,especially to the prophylaxis or treatment of systemic diseases in cats.In particular, the present invention relates to a method of prophylaxisor treatment of systemic diseases in cats, wherein the method comprisingadministration of a therapeutically effective amount of angiotensin IIreceptor 1 (AT-1) antagonist (sartan) to a cat in need of such atreatment.

BACKGROUND OF THE INVENTION

The prevalence of renal disease is high in aged cats, whereas chronicrenal failure is considered the most important one. The prevalence ofchronic kidney disease (CKD) in cats is reported to reach up to 20% with53% of cats were older than 7 years (Lefebre, Toutain 2004, J. Vet.Pharm. Therap. 27, 265-281; Wolf A M North. Am. Vet Congress 2006).Survival in cats with mild to moderate azotemia and extrarenal clinicalsigns (IRIS stage 2 & 3) ranged from 1 to 3 years. Early management andtherapy is considered to successfully influence prognosis for CKD (WolfA M North Am. Vet Congress 2006)

Chronic renal failure (CRF), at least in its final stage is, regardlessof the underlying causes, characterized by irreversible structurallesions of the kidney. Thereby, progressive irreversible lesionsinitially localized to one portion of the nephron (e.g. glomeruli,peritubular capillaries, tubules or interstitial tissue), are eventuallyresponsible for the development of lesions in the remaining, butinitially unaffected portions of nephrons due to their functionalinterdependencies. New nephrons cannot be formed to replace othersirreversibly destroyed by disease. In a study of biopsy findings in catswith primary renal azotemia, tubulointerstitial nephritis was observedin 70%, glomerulonephropathy occurred in 15%, lymphoma in 11% andamyloidosis was observed in 2% of the samples. CRF is recognized byreduced kidney function or the presence of kidney damage (Polzin,Osborne, Ross 2005 in: Ettinger S J, Feldman C E (eds.) Textbook ofVeterinary Internal Medicine, 6^(th), Vol 2. Chapter 260, 1756-1785).

Angiotensin II plays an important part in pathophysiology, particularlyas the most potent agent for increasing blood pressure in humans. It isknown that in addition to its effect of raising blood pressureAngiotensin II also has growth-promoting effects which contribute toleft ventricular hypertrophy, vascular thickening, atherosclerosis,renal failure and stroke. In small animals, inhibition of the effects ofAngiotensin II, via either ACE inhibitors have been shown to exhibitrenoprotective effects through their simultaneous capacity to decreaseblood pressure and control proteinuria.

Current therapy aims to delay the progression of the disease in cats byimproving renal function, especially glomerular function by maintainingglomerular perfusion. This includes dietary protein restriction,modification of dietary lipid intake, phosphate restriction andtreatment with angiotensin-converting enzyme (ACE) inhibitors (P. J.Barber (2004) The Kidney, in: Chandler E A, Gaskell C J, Gaskell R M,(eds.) Feline Medicine and Therapeutics, 3rd edition, BlackwellPublishing, Oxford, UK).

ACE inhibitors, especially enalapril, benazepril, imidapril andramipril, have been initially developed in small animal medicine tocontrol chronic heart failure (CHF). Based on the pathophysiologicalrole of the renin-angiotensin-aldosterone system (RAAS) in progressionof chronic heart failure and in progression of renal damage, theseagents have been shown to be useful in the treatment of chronic kidneydisease (CKD) in order to delay progression of disease and reducemorbidity and suffering in small animals, including cats. Sound evidencefor this is probably the recent approval of benazepril in Europe for thetreatment of feline CRF (Lefebre Toutain, 2004 J Vet Pharm Therap 27,265-281). However, the renoprotection of ACE inhibitor was likelymediated by the effect on proteinuria rather than by blood pressurereduction. This has been shown for ramipril, since the effect on bloodpressure was comparable to that of placebo while the proteinuria wasreduced (Remuzzi et al., 2006 J Clin Invest 116, (2) 288-296).

From a clinical point of view, ACE inhibitors are not the preferredtarget to block the RAAS because of the lack of specificity forAngiotensin I and the “angiotensin escape” phenomen; where alternateenzymatic pathways such a cathepsin, trypsin or the heart chymase canalso convert Angiotensin I. Moreover, during long term treatment withACE inhibitors, ACE activity is upregulated and Angiotensin I levels arehigh due the stimulated renin secretion (Burnier & Brunner 2000 TheLancet, 355 637-645).

Thus, one objective of the present invention consists in providing a newtherapeutic approach for the treatment or prophylaxis of cats againstchronic kidney disease.

A further more general aspect of the present invention consists inproviding a new therapeutic approach for the treatment or prophylaxis ofcats against systemic diseases; preferably against systemic diseaseswhich are related to Angiotensin II or associated with therenin-angiotensin-aldosterone system (RAAS).

DESCRIPTION OF THE INVENTION Description of Figures

FIG. 1: Inhibition of blood pressure increase by angiotensin II receptor1 antagonist

DETAILED DESCRIPTION OF THE INVENTION

Before the embodiments of the present invention it shall be noted thatas used herein and in the appended claims, the singular forms “a”, “an”,and “the” include plural reference unless the context clearly dictatesotherwise. Thus, for example, reference to “a preparation” includes aplurality of such preparations, reference to the “carrier” is areference to one or more carriers and equivalents thereof known to thoseskilled in the art, and so forth. Unless defined otherwise, alltechnical and scientific terms used herein have the same meanings ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All given ranges and values may vary by 1 to 5%unless indicated otherwise or known otherwise by the person skilled inthe art, therefore, the term “about” was omitted from the description.Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of the presentinvention, the preferred methods, devices, and materials are nowdescribed. All publications mentioned herein are incorporated herein byreference for the purpose of describing and disclosing the substances,excipients, carriers, and methodologies as reported in the publicationswhich might be used in connection with the invention. Nothing herein isto be construed as an admission that the invention is not entitled toantedate such disclosure by virtue of prior invention.

The solution to the above technical problem is achieved by thedescription and the embodiments characterized in the claims.

To date, the use of angiotensin II receptor 1 antagonists (sartans) incats is not described for any indication. Blockage of angiotensin IIreceptor 1 is a treatment concept which differs from blockage ofangiotensin converting enzyme as known from the ACE-inhibitors. Receptorblockage is more specific and complete and further downstream in thephysiologic cascade of the RAAS system. The present invention is basedon various unexpected findings:

It was surprisingly found that cats tolerate a pharmacodynamicallyeffective dose of sartans. In a open-label study in nondiabetic,hypertensive human patients with proteinuric nephropathies the effectson renal outcome of low (80 mg once daily) and high dose (80 mg twicedaily) telmisartan were compared. The results reinforced the conceptthat more effective RAAS inhibition achieved by a high dose of 160 mgdaily. This dose corresponds to a plasma level of about 2800±2400 ng/ml(Cmax±SD), which exceeds the no-effect doses in toxicities studies inanimals such as dogs and rats. (Investigator broschure 1994, data onfile) The resulting dose of about 2 to 3 mg/Kg body weight and day wasthus expected to be toxic in cats. Pilot-toxicity studies havesurprisingly shown that such a dose (up to 3 mg/kg) is well tolerable incats.

Moreover, it was found that sartans effectively blocks the angiotensinII receptor 1 also in cats. This finding was all the more unexpected, asthe absolute bioavailability in cats is very low and the mean residencetime and plasma half life are rather short in cats as compared to humanbeings. The oral bioavailability was calculated to 33.6% as compared tohuman beings. The mean t_(max) oral was 0.44 hours and the C_(max) oralwas 138.1 ng/ml. The mean t_(1/2) oral was 2.17 hours. The meanAUC→˜oral was calculated to 150 (ng×h/ml), and the mean V/f oral was20.4 l/kg. The mean AUC→˜intravenous was calculated to 385 (ng×h/ml).The mean t_(1/2) intravenous was 2.25 hours and the mean V/f oral was8.8 l/kg. From this information, which was newly generated, it can beconcluded that sartans, preferably telmisartan, can be used to treatcats with systemic diseases, preferably with chronic kidney disease,such as for example chronic renal failure, including chronic renalinsufficiency.

TABLE 1 Abbreviations Abbreviation Pharmacokinetic parameters AUC areaunder the plasma concentration time curve C max maximum measured plasmaconcentration V/f Volume of distribution (V) whereas f is the absolutebioavailability MRT mean residence time t½ terminal half-live t max timeto reach Cmax

Thus, according to one embodiment, the present invention relates to amethod for the prophylaxis or treatment of a systemic disease in cats,wherein the method comprising administration of a therapeuticallyeffective amount of angiotensin II receptor 1 (AT-1) antagonist (sartan)to that cat in need of such a treatment.

The term “systematic disease” as used herein means but is not limited tocardiovascular such as dilated cardiomyopathy (DCM), mitral valveinsufficiency (MI), hypertrophic cardiomyopathy (HCM); and otheracquired or hereditary heart diseases, e.g. cardiopulmonary diseases,systemic hypertension for example hypertension associated with renaldiseases, chronic renal failure and other vascular diseases, ormetabolic disorders such as diabetes mellitus. Thus, according toanother aspect, the present invention relates to a method for theprophylaxis or treatment of a systemic disease in cats by theadministration of therapeutically effective amount of said angiotensinII receptor 1 (AT-1) antagonist (sartan) to that cat, wherein thesystemic disease is selected from the group of cardiovascular diseases,such as dilated cardiomyopathy (DCM), mitral valve insufficiency (MI),hypertrophic cardiomyopathy (HCM) and other acquired or hereditary heartdiseases, systemic hypertension, for example hypertension associatedwith renal diseases, chronic renal failure and other vascular diseases,metabolic disorders like diabetes is mellitus.

In humans, angiotensin II receptor 1 (AT1 receptor antagonists (sartans)are known to significantly reduces proteinuria in both diabetic andnon-diabetic patients, even in those with mild to moderate chronic renalfailure (CRF). Moreover, there is published evidence for the efficacioususe of AT1 receptor antagonists for treatment of nephropathies in typeII diabetes Cupisti A, et al., 2003, Biomed Pharmacother; 57(3-4):169-172; Rysava R, et al., 2005, Press Monit; (10(4):207-213;WO92/10182). In cats tubulointerstitial nephritis is reported to be themajor causative (>70%) finding for CRF whereas in human beings and dogsglomerulonephropathy is more prominent compared to cats. Glomerularlesions are more often seen in dogs and humans and consequently theclinical finding of moderate to marked proteinuria, resulting from lossof glomerular permselectivity, is more common in dogs and humans.Tubulointerstitial nephritis as seen in cats showed less proteinuria.Proteinuria is recognized as an important predictor of diseaseprogression in humans and dogs with spontaneous kidney disease andreduction of proteinuria is associated with improved outcome in clinicaltrials to show the renoprotective effects of blocking the RAAS by eitherACE or ARBs in human suffering from nephropathy (Karalliede & Viberti, JHuman Hypertension 2006). Due to the fact that there is less proteinuriain cats because of the tubulointerstitial origin of CRF, the reductionof proteinuria as renoprotective effect in delaying progression of CRFmight be expected to be less important in this species. However, in aclinical field trial an independent and significant correlation betweenproteinuria (determined as UPC) and survival in cats suffering from CRFhave been reported. Surprisingly, even in azotemic cats with only minorproteinuria (acc. to IRIS, UPC <0.25) this correlation was evident(Syme, Elliot 2006, J Vet Intern Med, 20, 528-535).

Thus, according to a preferred embodiment the systemic disease ischronic kidney disease, preferably chronic renal failure, e.g. asdefined as stage II to IV in Table 2.

The diagnosis of reduced kidney function such as chronic renal failureis based on exclusion of pre- and postrenal causes and standard bloodmarkers, e.g. urea and creatinine in plasma or serum. Abnormalconcentrations of these parameters are described as azotemia. Standardurine markers of reduced kidney function include urine specific gravity,proteinuria and others (Polzin D J, Osborne C A, Ross S, 2005: ChronicKidney Disease, In: Ettinger S J, Feldman E C (ed.) Textbook ofVeterinary Internal Medicine 6^(th) edition, WB. Saunders Company,Philadelphia, USA). The international renal interest society (IRIS) hasproposed a staging system based on azotemia to define CRF patients(Polzin DJ, 2006: Treating feline kidney disease: an evidence-basedapproach, Proceedings of The North American Veterinary Conference). Themain category for staging being plasma creatinine [mg/dl], which iscompleted by two subcategories independent from stage, urineprotein:creatinine ratio (UPC) and blood pressure [mmHg]. With theapplied system, feline patients are staged along a continuum ofprogressive kidney disease.

TABLE 2 Stages of feline chronic kidney disease Subcategory PlasmaSubcategory systolic blood creat- UPC pressure (mmHg, inine (independentindependent Stage (mg/dl) Comments from stage) from stage) I <1.6Non-azotemic: some <0.2 = Non- <150 = minimal other renal abnor-proteinuric risk of end-organ mality is present 0.2-0.4 = damage II1.6-2.8 Mildly azotemic: Borderline 150-159 = low usually mildproteinuric risk of end-organ clinical signs >0.4 = damage III 2.9-5.0Moderately Proteinuric 160-179 = azotemic: moderate many extra-renalrisk of end-organ clinical signs damage IV >5.0 Severly azotemic: ≧180 =high invasive life risk of end-organ support methods damage required

Thus, according to a further embodiment, the present invention relatesto a method for the prophylaxis or treatment of chronic renal failure incats, wherein the method comprising administration of a therapeuticallyeffective amount of angiotensin II receptor 1 (AT-1) antagonist (sartan)to that cat in need of such a treatment and wherein said chronic renalfailure is characterized by any one of the clinical manifestations aslisted in table 2, or any combination thereof. For example, the presentinvention relates to a method for the prophylaxis or treatment of catshaving an plasma creatine of ≧1.6 (mg/dl of blood), and/or having aproteinuric of ≧0.2 (subcategory UPC), wherein the method comprisingadministration of a therapeutically effective amount of angiotensin IIreceptor 1 (AT-1) antagonist (sartan) to that cat in need of such atreatment.

A comprehensive list of angiotensin II receptor antagonists can be foundon pages 2 to 22 of WO 92/10182 and pages 7 to 18 of WO 95/26188, whichall are incorporated herein by reference. Angiotensin II receptorantagonists are described inter alia in EP-A-253310, EP-A-323841,EP-A-324377, EP-A-420237, EP-A-443983, EP-A-459136, EP-A-475206,EP-A-502314, EP-A-504888, EP-A-514198, WO 91/14679, WO 93/20816, WO02/092081, U.S. Pat. No. 4,355,040, U.S. Pat. No. 4,880,804 and U.S.Pat. No. 6,028,091. Forms which are frequently mentioned are sartans,such as candesartan, eprosartan, irbesartan, losartan, olmesartan,tasosartan, telmisartan or valsartan. Those which are particularlypreferred according to the present invention are irbesartan, losartanund telmisartan. All of these sartans, or pharmaceutical salts orpolymorphs thereof are well known to a person skilled in the art, andits use is within the meaning of the present invention.

Thus the present invention relates to a method for the prophylaxis ortreatment of cats suffering from a systemic disease, preferably fromchronic kidney disease, e.g. chronic renal failure, wherein the methodcomprising administration of a therapeutically effective amount ofangiotensin II receptor 1 (AT-1) antagonist (sartan) to that cat in needof such a treatment and wherein the angiotensin II receptor 1 (AT-1)antagonist (sartan) is selected from the group consisting of:candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan,telmisartan or valsartan, preferably of irbesartan, losartan undtelmisartan.

Telmisartan is an angiotensin II receptor antagonist developed for thetreatment of hypertension and other medical indications as disclosed inEP-A-502314. Its chemical name is4′-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-ylmethyl]-biphenyl-2-carboxylicacid having the following structure:

Telmisartan is already sold on the market under the trade name Micardis®(Boehringer Ingelheim, Germany) for treatment/prophylaxis of humans. Itexists in two polymorphic forms as disclosed in WO 00/43370, U.S. Pat.No. 6,358,986 and U.S. Pat. No. 6,410,742. Sodium salts of telmisartanand its solvate, hydrate, and hemihydrate are disclosed in WO 03/037876.

Thus, according to a further embodiment, the present invention relatesto a method for the prophylaxis or treatment of a systemic disease incats, preferably of chronic kidney disease, e.g. chronic renal failure,wherein the method comprising administration of a therapeuticallyeffective amount of telmisartan or pharmaceutically acceptable saltthereof, preferably of a telmisartan as mentioned above. More preferablysaid telmisartan is Micardis®.

As already mentioned above, it has been surprisingly found that use oftelmisartan effectively inhibits the angiotensin II receptor pressureresponse in cats. Moreover, it has been surprisingly found that doses ofless than 0.05 mg telmisartan per kg body weight of cat led to aninhibition of the blood pressure response of about 75% in the majorityof the tested cats. Moreover, a study in laboratory cats was establishedto investigate the Angiotensin II induced increase in diastolic bloodpressure prior to and after administration of telmisartan. This test wasestablished to estimate the potency as well as the duration of action ofsartans, in particular of telmisartan in cats. Approximately 24 hoursafter the last oral dosing, diastolic blood pressure responses toincreasing intravenous doses of Angiotensin II were significantlyreduced when the target dose of telmisartan was compared with Placebo.Thus it could be concluded that administration of the target dose,despite the short elimination half-life and bioavailability, in the catgiven once daily is capable to exhibit the intended pharmacodynamicaction and duration.

Thus, according to another aspect, the present invention relates to amethod for the prophylaxis or treatment of a systemic disease in cats,preferably of chronic kidney disease, e.g. chronic renal failure,wherein the method comprising administration of a therapeuticallyeffective amount of angiotensin II receptor 1 (AT-1) antagonist(sartan), preferably telmisartan or pharmaceutically acceptable saltthereof, to that cat in need of such a treatment, wherein thetherapeutically effective amount of such angiotensin II receptor 1(AT-1) antagonist is about 0.01 to about 10 mg/kg of body weight.Preferably, said therapeutically effective amount of such angiotensin IIreceptor 1 (AT-1) antagonist is about 0.05 to about 8 mg/kg of bodyweight, even more preferably about 0.1 to about 5 mg/kg of body weight,even more preferably about 0.2 to about 4 mg/kg of body weight, evenmore preferably about 0.3 to about 3 mg/kg of body weight, even morepreferably about 0.4 to about 2.5 mg/kg of body weight, even morepreferably about 0.5 to about 2 mg/kg of body weight, most preferredabout 0.75 to about 1.5 mg/kg of body weight. Thus, said therapeuticallyeffective amount of such angiotensin II receptor 1 (AT-1) antagonist isfor example 0.01, 0.02, 0.03, . . . 0.08, 0.09, 0.1, etc.; 0.11, 0.12,0.13, . . . 0.18, 0.19, 0.2, etc.; 0.21, 0.22, 0.23, . . . 0.28, 0.29,0.3 etc. . . . ; 0.81, 0.82, 0.83, . . . 0.88, 0.89, 0.9 etc.; 0.91,0.92, 0.93, . . . 0.98, 0.99, 1.0 etc.; 1.01, 1.02, 1.03, . . . 1.08,1.09, 1.1 etc.; . . . 1.2, 1.3, . . . 1.8, 1.9, 2.0 etc.; 2.1, 2.2, 2.3,. . . 2.8, 2.9, 3.0 etc.; . . . ; 8.1, 8.2, 8.3, . . . 8.8, 8.9, 9.0etc.; 9.1, 9.2, 9.3, . . . 9.8, 9.9, 10 mg/kg of body weight.Angiotensin II receptor 1 (AT-1) antagonist, preferably telmisartan maybe administered once twice or trice a day in a daily dosage as mentionedabove.

In cases when angiotensin II receptor 1 (AT-1) antagonist isadministered by parenteral route, said angiotensin II receptor 1 (AT-1)antagonist, preferably telmisartan is administered in a dosage of about0.01 to about 4 mg/kg of body weight. Preferably, said therapeuticallyeffective amount of such angiotensin II receptor 1 (AT-1) antagonist isabout 0.05 to about 3 mg/kg of body weight, even more preferably about0.1 to about 2.5 mg/kg of body weight, even more preferably about 0.15to about 2.0 mg/kg of body weight, even more preferably about 0.2 toabout 1.5 mg/kg of body weight, most preferred about 0.25 to about 1.25mg/kg of body weight. Thus, said therapeutically effective amount ofsuch angiotensin III receptor 1 (AT-1) antagonist is for example 0.01,0.02, 0.03, . . . 0.08, 0.09, 0.1, etc.; 0.11, 0.12, 0.13, . . . 0.18,0.19, 0.2, etc.; 0.21, 0.22, 0.23, . . . 0.28, 0.29, 0.3 etc. . . . ;0.81, 0.82, 0.83, . . . 0.88, 0.89, 0.9 etc.; 0.91, 0.92, 0.93, . . .0.98, 0.99, 1.0 etc.; 1.01, 1.02, 1.03, . . . 1.08, 1.09, 1.1 etc.; . .. 1.1, 1.2, 1.3, . . . 1.8, 1.9, 2.0 etc.; 2.1, 2.2, 2.3, . . . 2.8,2.9, 3.0 etc.; 3.1, 3.2, 3.3, . . . 3.8, 3.9, 4 mg/kg of body weight.Angiotensin II receptor 1 (AT-1) antagonist, preferably telmisartan maybe administered once twice or trice a day in a daily dosage as mentionedabove.

In cases when angiotensin II receptor 1 (AT-1) antagonist, preferablytelmisartan is administered by oral, rectal, nasal or inhalative route adosage of about 0.03 to about 10 mg/kg of body weight is preferred.Preferably, said therapeutically effective amount of such angiotensin IIreceptor 1 (AT-1) antagonist is about 0.10 to about 8 mg/kg of bodyweight, even more preferably about 0.20 to about 7.5 mg/kg of bodyweight, even more preferably about 0.25 to about 7.0 mg/kg of bodyweight, even more preferably about 0.25 to about 6.0 mg/kg of bodyweight, most preferred about 0.25 to about 5 mg/kg of body weight. Thus,said therapeutically effective amount of such angiotensin II receptor 1(AT-1) antagonist is for example 0.03, 0.04, 0.05, . . . 0.08, 0.09,0.1, etc.; 0.11, 0.12, 0.13, . . . 0.18, 0.19, 0.2, etc.; 0.21, 0.22,0.23, . . . 0.28, 0.29, 0.3 etc. . . . ; 0.81, 0.82, 0.83, . . . 0.88,0.89, 0.9 etc.; 0.91, 0.92, 0.93, . . . 0.98, 0.99, 1.0 etc.; 1.01,1.02, 1.03, . . . 1.08, 1.09, 1.1 etc.; . . . 1.1, 1.2, 1.3, . . . 1.8,1.9, 2.0 etc.; 2.1, 2.2, 2.3, . . . 2.8, 2.9, 3.0 etc.; . . . ; 8.1,8.2, 8.3, . . . 8.8, 8.9, 9.0 etc.; 9.1, 9.2, 9.3, . . . 9.8, 9.9, 10mg/kg of body weight. Telmisartan may be administered once twice ortrice a day in a daily dosage as mentioned above.

According to another aspect of the invention, the present inventionrelates a method for the prophylaxis or treatment of a systemic diseasein cats, preferably of chronic kidney disease, e.g. chronic renalfailure, wherein the method comprising administration of atherapeutically effective amount of angiotensin II receptor 1 (AT-1)antagonist (sartan), preferably telmisartan or pharmaceuticallyacceptable salt thereof, to that cat in need of such a treatment,wherein the therapeutically effective amount of such angiotensin IIreceptor 1 (AT-1) antagonist is administered in a therapeuticallyeffective amount that result in an cumulative intravenous concentrationof at least 0.025 mg/kg of body weight (bw) Preferably, said angiotensinII receptor 1 (AT-1) antagonist (sartan), preferably telmisartan isadministered to an cumulative intravenous concentration of at least 0.05mg/kg of bw, more preferably of 0.1 mg/kg of bw, even more preferably0.15 mg/kg of bw even more preferably 0.2 mg/kg of bw, even morepreferably 0.25 mg/kg of bw, even more preferably 0.40 mg/kg of bw, evenmore preferably 0.5 mg/kg of bw, even more preferably 0.75 mg/kg of bw,even more preferably 1 mg/kg of bw. Upper limits of cumulativeintravenous concentration of about 1 mg/kg of bw are well tolerable,however, cumulative intravenous concentrations of up to 5, 4, 3 and 2mg/kg of bw are also within the meaning of the present invention as wellas any further higher non-toxic cumulative intravenous concentration ofsaid angiotensin II receptor 1 (AT-1) antagonist (sartan). A personskilled in the art, in view of the teaching given herein, is entitled toestimate that upper non-toxic cumulative intravenous concentration bystandard techniques.

Optionally, the angiotensin II receptor 1 (AT-1) antagonist (sartan),preferably telmisartan can be administered in combination with otherdrugs. Such other drugs are, for example Ca-channel blockers (e.g.Amlodipine), beta-blockers (e.g. Atenolol, Carvediol),cardiotonic-Ca-sensitising agents (e.g. Pimobendan, Levosimendan),selective If-current inhibitors (i.e. Cilobradine, Ivabradine), ACEinhibitors (e.g. ramipril, benazepril, enalapril); anti-obesity drugs(such as Amphetamine derivatives, Sibutramine, Orlistat, Rimonabat) andthe like. Thus, according to another aspect, the present inventionrelates to a method for the prophylaxis or treatment of a systemicdisease in cats, preferably of chronic kidney disease, e.g. chronicrenal failure, wherein the method comprising administration of atherapeutically effective amount of angiotensin II receptor 1 (AT-1)antagonist (sartan), preferably telmisartan or pharmaceuticallyacceptable salt thereof, together with another active substance, to thatcat in need of such a treatment, wherein said further active substanceis a Ca-channel blocker (e.g. Amlodipine), beta-blocker (e.g. Atenolol,Carvediol), cardiotonic-Ca-sensitising agent (e.g. Pimobendan,Levosimendan), selective If-current inhibitor (i.e. Cilobradine,Ivabradine), ACE inhibitor (e.g. ramipril, benazepril, enalapril); ananti-obesity drug (such as Amphetamine derivatives, Sibutramine,Orlistat, Rimonabat) and the like.

Telmisartan and the other active compounds can be orally administered ina wide variety of different dosage forms, i.e., they may be formulatedwith various pharmaceutically acceptable inert carriers in the form oftablets, capsules, lozenges, troches, hard candies, powders, sprays,aqueous suspensions, elixirs, syrups, and the like. Such carriersinclude solid diluents or fillers, sterile aqueous media and variousnon-toxic organic solvents. Moreover, such oral pharmaceuticalformulations can be suitably sweetened and/or flavoured by means ofvarious agents of the type commonly employed for such purposes. Ingeneral, the compounds of this, invention are present in such oraldosage forms at concentration levels ranging from about 0.5% to about90% by weight of the total composition, in amounts which are sufficientto provide the desired unit dosages. Other suitable dosage forms for thecompounds of this invention include controlled release formulations anddevices well known to those who practice in the art.

For purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and calciumphosphate may be employed along with various disintegrants such asstarch and preferably potato or tapioca starch, alginic acid and certaincomplex silicate, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatine and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc or compositions of a similar type may also be employed as fillersin soft and hard-filled gelatine capsules; included lactose or milksugar as well as high molecular weight polyethylene glycols. Whenaqueous suspensions and/or elixirs are desired for oral administration,the essential active ingredient therein may be combined with varioussweetening or flavouring agents, colouring matter or dyes and, if sodesired, emulsifying agents and/or water, ethanol, propylene glycol,glycerine and various like combinations thereof.

For purposes of parenteral administration, solutions of the compounds insesame or peanut oil or in aqueous propylene glycol may be employed, aswell as sterile aqueous solutions of the corresponding pharmaceuticallyacceptable salts. Such aqueous solutions should be suitably buffered ifnecessary, and the liquid diluent rendered isotonic with sufficientsaline or glucose. These particular aqueous solutions are especiallysuitable for intravenous, intramuscular and subcutaneous injectionpurposes. In this connection, the sterile aqueous media employed arereadily obtained by standard techniques well known to those skilled inthe art. For instance, distilled water is ordinarily used as the liquiddiluent and the final preparation is passed through a suitable bacterialfilter such as a sintered glass filter or a diatomaceous earth orunglazed porcelain filter. Preferred filters of this type include theBerkefeld, the Chamberland and the Asbestos Disk-Metal Seitz filter,wherein the fluid is sucked into a sterile container with the aid of asuction pump. The necessary steps should be taken throughout thepreparation of these inject-able solutions to insure that the finalproducts are obtained in a sterile condition.

For purposes of transdermal administration, the dosage form of theparticular compound or compounds may include, by way of example,solutions, lotions, ointments, creams, gels, suppositories,rate-limiting sustained release formulations and devices therefore. Suchdosage forms comprise the particular compound or compounds and mayinclude ethanol, water, penetration enhancer and inert carriers such asgel-producing materials, mineral oil, emulsifying agents, benzyl alcoholand the like.

These preformulated combinations of active substances are generallyincorporated with one or more formulation adjuvants such as mannitol,sorbitol, xylitol, saccharose, calcium carbonate, calcium phosphate,lactose, croscarmellose sodium salt (cellulose carboxymethylether sodiumsalt, cross-linked), crospovidone, sodium starch glycolate,hydroxypropylcellulose (low-substituted), maize starch,polyvinylpyrrolidone, copolymers of vinylpyrrolidone with other vinylderivatives (copovidone), hydroxypropylcellulose,hydroxypropylmethylcellulose, microcrystalline cellulose or starch,magnesium stearate, sodium stearylfumarate, talc,hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetatephthalate, polyvinyl acetate, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearylalcohol, carboxy-methylcellulose or fatty substances such as hard fat orsuitable mixtures thereof, into conventional galenic preparations suchas plain or coated tablets, capsules, powders, suspensions orsuppositories.

Tablets may be obtained for example by mixing the active substance orsubstances with one or more excipients and subsequently compressingthem. The tablets may also consist of several layers. Examples ofexcipients are

-   -   inert diluents such as mannitol, sorbitol, xylitol, saccharose,        calcium carbonate, calcium phosphate and lactose;    -   disintegrants such as croscarmellose sodium salt (cellulose        carboxymethylether sodium salt, cross-linked), crospovidone,        sodium starch glycolate, hydroxypropylcellulose        (low-substituted) and maize starch;    -   binders such as polyvinylpyrrolidone, copolymers of        vinylpyrrolidone with other vinyl derivatives (copovidone),        hydroxypropylcellulose, hydroxypropylmethylcellulose,        microcrystalline cellulose or starch;    -   lubricants such as magnesium stearate, sodium stearyl fumarate        and talc;    -   agents for achieving delayed release such as        hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose        acetate phthalate and polyvinyl acetate; and    -   pharmaceutically permitted colourings such as coloured iron        oxides.

Furthermore, if telmisartan is used in combination with another drugused for the prophylaxis or treatment of a systemic disease, preferablyof chronic kidney disease, e.g. chronic renal failure in cats, thepharmaceutical composition according to the invention may be a kit ofparts which comprises

-   -   (a) a first containment containing a pharmaceutical composition        comprising a therapeutically effective amount of telmisartan or        a physiologically acceptable salt thereof and one or more        pharmaceutically acceptable diluents and/or carriers; and    -   (b) a second containment containing another drug used for the        prophylaxis or treatment of a systemic disease, preferably        chronic renal failure, or a physiologically acceptable salt        thereof and one or more pharmaceutically acceptable diluents        and/or carriers.

A preferred kit of parts comprises one or more Ca-channel blockers (e.g.Amlodipine), beta-blockers (e.g. Atenolol, Carvediol),cardiotonic-Ca-sensitising agents (e.g. Pimobendan, Levosimendan),selective If-current inhibitors (i.e. Cilobradine, Ivabradine), ACEinhibitors (e.g. ramipril, benazepril, enalapril); anti-obesity drugs(such as Amphetamine derivatives, Sibutramine, Orlistat, Rimonabat) andthe like, in the second containment.

According to a further aspect, the present invention also relates to theuse of an angiotensin II receptor 1 (AT-1) antagonist (sartan),preferably of telmisartan for the manufacture of a pharmaceuticalcomposition comprising a therapeutically effective amount of saidangiotensin II receptor 1 (AT-1) antagonist for the treatment of asystemic disease in cats.

Preferably the systemic disease is selected from the group ofcardiovascular diseases, such as dilated cardiomyopathy (DCM), mitralvalve insufficiency (MI), hypertrophic cardiomyopathy (HCM) and otheracquired or hereditary heart diseases, systemic hypertension, forexample hypertension associated with renal diseases, chronic kidneydisease and other vascular diseases, metabolic disorders like diabetesmellitus. As mentioned above, chronic kidney disease, preferably chronicrenal failure is most preferred.

Preferred sartans are those mentioned in an exemplarily manner supra.Most preferred is the use of telmisartan or any pharmaceuticallyacceptable salt thereof, such as Micardis®. The preferred doses whichcan be used according to the invention are those mentioned supra.Preferred administration routes are orally, bucally, parenterally,nasally, rectally or topically, whereas the oral administration beingmost preferred. Parenteral administration may include subcutaneous,intravenous, intramuscular and intrasternal injections and infusiontechniques.

EXAMPLES

The following examples serve to further illustrate the presentinvention; but the same should not be construed as a limitation of thescope of the invention disclosed herein.

Example 1

The aim of this exploratory study was to investigate the pharmacokineticbehaviour in plasma and the absolute bioavailability of telmisartan inmale and female cats following a single oral or intravenousadministration.

Four clinically healthy male and female domestic short hair cats(HsdCpb: CADS) with a body weight range of 2.6-4.2 kg were used in thisstudy. The animals were randomly allocated to 2 groups, 2 animals pergroup. The study was designed as a 2×2 cross-over trial (i.e. twoperiods, days 1 and 15) in which the test article telmisartan was givenby single oral or intravenous administration at a dose of 1 mg/kg bodyweight.

Blood samples were drawn at 0 h (i.e. prior to treatment), 5 (after i.v.injection only), 15, 30 and 60 min as well as 2, 4, 8, 24, 72 and 96 hafter each treatment. Clinical observations were also conducted at thesetime points. Plasma samples were sent to the analytical laboratory andanalysed there using a validated method. The plasma levels measured ineach animal were subjected to various pharmacokinetic calculations.

The results of this study may be summarised as follows:

No specific clinical signs were noted during the entire course of thestudy. Pharmacokinetic analyses for telmisartan revealed the followingresults:

Route of Administration Parameter oral i.v. t max [hour] mean 0.438 — Cmax [ng/ml] mean 138.10 — AUC 0 → ∞ mean 150.426 384.751 [ng · h/ml] AUC0→ ∞ mean 138.598 375.945 [ng · h/ml] t½ [hour] mean 2.169 2.252 Cl/f orCl [ml/min · kg] mean 171.588 45.535 V/f or V [l/kg] mean 20.453 8.856MRT [hour] mean 1.969 0.789

The points estimate for the absolute bioavailability were 0.316 for AUC0→t and 0.336 for AUC 0→∞ with respective 95% confidence intervals of0.086-1.165 and 0.090-1.245. Individual data showed that thebioavailability was clearly lower in animal no. 101 (i.e. 0.116 for AUC0→∞) in comparison with the other animals (i.e. 0.387-0.582).

The test article telmisartan was well tolerated after a single oral orintravenous administration to cats at a dose of 1 mg/kg body weight.

Mean plasma concentrations increased until 15-30 min after oraladministration of telmisartan and declined rapidly afterwards. Noquantifiable plasma concentrations could be found at 24 h after bothroutes, orally and intravenously.

The absolute bioavailability after oral administration was found to be33%.

Example 2

The aim of this study was to investigate the effects of an escalatingintravenous dose of telmisartan on the blood pressure response ofanaesthetised cats after administration of angiotensin II. Theoriginally intended endpoint of the study was to find a dose oftelmisartan which inhibits ≧90% of the angiotensin blood pressureresponse.

Four clinically healthy adult male and female domestic short hair cats(HsdCpb: CADS) with a body weight range of 2.5-3.5 kg were used in thisstudy. The animals were anaesthetised with sodium pentobarbital andanaesthesia was sustained by continuous infusion of diluted anaesthetic.A catheter was inserted into a carotid artery and connected to apressure transducer for registration of the arterial pressure. Anothercatheter was placed into the femoral vein for administration ofangiotensin II (A2) or the test article telmisartan. The systolic anddiastolic blood pressure [mmHg] in the carotid artery were recorded andanalysed at discrete intervals as described below.

At first, the diastolic blood pressure was registered 6 times every 5minutes. The mean of these 6 measurements were set as the baseline bloodpressure. Then two bolus injections of A2 were administered at a dose of0.1 μg/kg in an interval of 10 min. The maximum increase in diastolicblood pressure obtained from the second A2-bolus relative to thebaseline blood pressure was taken as the control angiotensin II-bloodpressure response (i.e. reference value).

Five minutes after the reference value was obtained, the first injectionof telmisartan was administered. Thirty minutes later the diastolicblood pressure was recorded, immediately followed by bolus injection ofA2 at a dose of 0.1 μg/kg and the maximum increase in diastolic bloodpressure was obtained. This procedure was to be repeated accordinglyuntil the intended endpoint of the experiment (i.e. an A2-pressureresponse ≦10% of the control A2-pressure response corresponding to ≧90%inhibition) was reached. During the course of the experiment it had beenshown that the dose of telmisartan had to be increased at single timepoints in order to increase the effect. In addition, the endpoint of a90% inhibition could not be reached in 3 of 4 animals even after severalconsecutive steps as described above so that the experiment wasterminated in these individual animals before. At the end of theexperiment, the anaesthetised animals were euthanized with an overdoseof sodium pentobarbital.

The results of this study may be summarised as follows (see FIG. 1):

The mean baseline diastolic blood pressure of the individual animalsranged from 82-99 mmHg and the control angiotensin II-blood pressureresponse was between 34 and 63 mmHg.

After treatment with telmisartan, the response pattern was similar in 3animals (i.e. animal nos. 102, 151, 152). In these animals the maximalinhibition of the blood pressure increase relative to the controlangiotensin II-blood pressure response was roughly 80-95% in contrast to50% inhibition in animal no. 101.

However, the final cumulative dose of the test article was only 0.1mg/kg in this animal whereas this dose ranged between 0.34 and 0.4 mg/kgin the other animals.

In animal no. 101 the maximum effect of 50% inhibition was reached at acumulative dose of 0.05 mg/kg. In animal nos. 102 and 152 a 73%inhibition was already reached after the 1^(st) dose of 0.04 and 0.02mg/kg, respectively. In animal no. 151 the same inhibition of 73% wasreached at a cumulative dose of 0.04 mg/kg. In all 4 animals, furtherescalation of the dose did not produce markedly higher effects whichwere appropriately related to the increase of the dose.

In conclusion, escalating intravenous doses of the test articletelmisartan led to an inhibition of the diastolic blood pressureincrease in anaesthetised cats after administration of angiotensin II.

An inhibition of 73% was found at the cumulative dose of 0.04 mg/kgtelmisartan in 3 of 4 animals. In one animal, a maximum inhibition of50% was observed at a cumulative dose of 0.05 mg/kg. In all 4 animals,further dose escalations did not produce an appropriate dose responserelationship.

Example 3

The aim of this blinded controlled, randomised exploratory study was toinvestigate the safety of telmisartan in male and female cats afterrepeated oral administration over four weeks.

Twelve clinically healthy approximately 1 year old male and female,domestic short hair cats (HsdCpb: CADS) with a body weight range of2.5-5.1 kg were used in this study. The animals were allocated to 3groups, 4 animals per group. All animals were treated with the testarticle telmisartan or control article (i.e. placebo) once daily on days0 to 27. The test/control article was administered orally at threedifferent does levels of 0.0 (placebo; group I), 1 (group II) and 3(group III) mg telmisartan/kg body weight. The bottles with thetest/control article looked identical with the exception of the animalno. in order to achieve blinding.

Blood samples for haematology and clinical chemistry were collected fromthe animals on days-1 (i.e. prior to the first treatment) and again ondays 3, 7, 14, 28. Body weights were measured weekly andelectrocardiography recording were made on days-1, 14, 21 and 28. Adetailed physical examination including determination of rectaltemperature and respiratory rate was carried out on days −1, 7, 14, 22and 28. Systolic blood pressure (once daily) and heart rate (twicedaily) were determined five days per week beginning prior to treatmentuntil necropsy. The palatability of the administered article wasassessed at various time points throughout treatment using a scoringsystem. On day 28 of the study, all animals were subjected to necropsyand stomach and kidneys were examined histopathologically. Relevantparameters were analysed using appropriate statistical procedures.

The results of this study can be summarised as follows:

No clinical findings clearly attributable to the treatment with the testarticle were observed during the entire study period.

Although no significant differences were found the results of theassessment of the palatability might indicate a slightly impairedpalatability of the test article formulation. However, the palatabilitywas predominantly good or acceptable in the animals of both treatedgroups II and III.

Physical and ECG examinations did not reveal treatment-related findingsat all time points of investigation.

No significant differences were found in the body weights, rectaltemperature, respiratory and heart rates during the course of the study.

The systolic blood pressure was significantly lower in the treatedgroups II and III compared to the control group I on single occasionsafter initiation of treatment. In addition, differences of borderlinesignificance were found including the time before treatment. Changesfrom baseline did not reveal significant differences between treatedgroups and controls. However, the course of the mean values over timemight suggest a tendency of a slight reduction of the systolic bloodpressure in groups II and III compared to group I from day 20 onwards.

No treatment-related differences were found between treated groups andthe concurrent controls in the haematological and clinical chemistryparameters including the differential leukocyte count on each day ofexamination during the study. Urinalysis did also not provide evidenceof a treatment effect.

No animal showed any specific finding during necropsy.

Histopathology revealed a few findings in stomach and kidneys but therewere no histopathological findings considered to be associated with thetreatment.

Due to the exploratory nature of this study the number of animals pertreatment group was rather low. Taking this fact into consideration theresults of the present study may permit the following conclusions:

A slightly impaired palatability of the test article formulationcontaining telmisartan might be identified.

The course of the mean values over time might suggest a tendency of aslight reduction of the systolic blood pressure in the animals treatedwith telmisartan towards the end of the study period.

The test article telmisartan was well tolerated after repeated oraladministration over 4 weeks to cats at doses of 1 and 3 mg/kg bodyweight.

1. Use of an angiotensin II receptor 1 (AT-1) antagonist (sartan) for the manufacture of a pharmaceutical composition comprising a therapeutically effective amount of said angiotensin II receptor 1 (AT-1) antagonist for the treatment of a systemic disease in cats.
 2. The use according to claim 1, wherein the systemic disease is selected from the group of cardiovascular diseases, such as dilated cardiomyopathy (DCM), mitral valve insufficiency (MI), hypertrophic cardiomyopathy (HCM) and other acquired or hereditary heart diseases, systemic hypertension, e.g. hypertension associated with renal diseases, chronic kidney disease and other vascular diseases, metabolic disorders like diabetes mellitus.
 3. The use according to claim 1, wherein the systemic disease is chronic kidney disease.
 4. The use according to claim 1, wherein the angiotensin II receptor 1 (AT-1) antagonist is selected from the group consisting of: candesartan, eprosartan, irbesartan, losartan, tasosartan, telmisartan, valsartan, and a pharmaceutically acceptable salt thereof.
 5. The use according to claim 1, wherein the therapeutically effective amount of the angiotensin II receptor 1 (AT-1) antagonist is about 0.01 to about 5.0 mg/kg of body weight.
 6. The use according to claim 1, wherein the pharmaceutical composition is administered to a subject in need thereof by parenteral route in a dosage of about 0.01 to about 1 mg angiotensin II receptor 1 (AT-1) antagonist per kg of body weight or by oral, rectal, nasal or inhalative route in a dosage of about 0.03 to about 5.0 mg angiotensin II receptor 1 (AT-1) antagonist per kg of body weight.
 7. The use according to claim 1, wherein the pharmaceutical composition is administered to a subject in need thereof in a therapeutically effective amount that result in an cumulative intravenous dose of the angiotensin II receptor 1 (AT-1) antagonist of at least about 0.025 mg/kg of body weight.
 8. The use according to claim 1, wherein the pharmaceutical composition comprising the therapeutically effective amount of angiotensin II receptor 1 (AT-1) antagonist is administered together with at least one other drug to a cat in need of such a treatment.
 9. The use according to claim 8, wherein the other drug is selected from the group consisting of Ca-channel blockers (e.g. Amlodipine), beta-blockers (e.g. Atenolol, Carvediol), cardiotonic-Ca-sensitising agents (e.g. Pimobendan, Levosimendan), selective If-current inhibitors (i.e. Cilobradine, Ivabradine), ACE inhibitors (e.g. ramipril, benazepril, enalapril); anti-obesity drugs (such as Amphetamine derivatives, Sibutramine, Orlistat, Rimonabat).
 10. A method for the prophylaxis or treatment of a systemic disease in cats, wherein the method comprising administration of a therapeutically effective amount of angiotensin II receptor 1 (AT-1) antagonist (sartan) to that cat in need of such a treatment.
 11. The method according to claim 10, wherein the systemic disease is selected from the group of cardiovascular diseases, such as dilated cardiomyopathy (DCM), mitral valve insufficiency (MI), hypertrophic cardiomyopathy (HCM) and other acquired or hereditary heart diseases, systemic hypertension, chronic kidney disease and other vascular diseases, metabolic disorders like diabetes mellitus.
 12. The method according to claim 10, wherein the systemic disease is chronic kidney disease.
 13. The method according to claim 10, wherein the angiotensin II receptor 1 (AT-1) antagonist is selected from the group consisting of: candesartan, eprosartan, irbesartan, losartan, tasosartan, telmisartan, valsartan, and a pharmaceutically acceptable salt thereof.
 14. The method according to claim 10, wherein the therapeutically effective amount of the angiotensin II receptor 1 (AT-1) antagonist is about 0.01 to about 5.0 mg/kg of body weight.
 15. The method according to claim 10, wherein the angiotensin II receptor 1 (AT-1) antagonist is administered by parenteral route in a dosage of about 0.01 to about 1 mg/kg of body weight or by oral, rectal, nasal or inhalative route in a dosage of about 0.03 to about 5 mg/kg of body weight.
 16. The method according to claim 10, wherein the angiotensin II receptor 1 (AT-1) antagonist is administered in a therapeutically effective amount that result in an cumulative intravenous dose of at least 0.025 mg/kg of body weight.
 17. The method according to claim 10, wherein the method further comprises administration of at least one other drug to such cat in need of such a treatment.
 18. The method according to claim 17, wherein the other drug is selected from the group consisting of Ca-channel blockers (e.g. Amlodipine), beta-blockers (e.g. Atenolol, Carvediol), cardiotonic-Ca-sensitising agents (e.g. Pimobendan, Levosimendan), selective If-current inhibitors (i.e. Cilobradine, Ivabradine), ACE inhibitors (e.g. ramipril, benazepril, enalapril); anti-obesity drugs (such as Amphetamine derivatives, Sibutramine, Orlistat, Rimonabat). 